Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints

作者：Mikucki, M. E.; Fisher, D. T.; Matsuzaki, J.; Skitzki, J. J.; Gaulin, N. B.; Muhitch, J. B.; Ku, A. W.; Frelinger, J. G.; Odunsi, K.; Gajewski, T. F.; Luster, A. D.; Evans, S. S.^*

来源：Nature Communications, 2015, 6(1): 7458.

DOI：10.1038/ncomms8458

• INFILTRATING LYMPHOCYTES
• ADOPTIVE IMMUNOTHERAPY
• INDUCIBLE PROTEIN-10
• CHEMOKINE GRADIENTS
• ANTITUMOR IMMUNITY
• MELANOMA PATIENTS
• DENDRITIC CELLS
• EFFECTOR-CELLS
• CANCER MODEL
• LYMPH-NODE

T-cell trafficking at vascular sites has emerged as a key step in antitumour immunity. Chemokines are credited with guiding the multistep recruitment of CD8(+) T cells across tumour vessels. However, the multiplicity of chemokines within tumours has obscured the contributions of individual chemokine receptor/chemokine pairs to this process. Moreover, recent studies have challenged whether T cells require chemokine receptor signalling at effector sites. Here we investigate the hierarchy of chemokine receptor requirements during T-cell trafficking to murine and human melanoma. These studies reveal a non-redundant role for G(alpha i)-coupled CXCR3 in stabilizing intravascular adhesion and extravasation of adoptively transferred CD8(+) effectors that is indispensable for therapeutic efficacy. In contrast, functional CCR2 and CCR5 on CD8(+) effectors fail to support trafficking despite the presence of intratumoral cognate chemokines. Taken together, these studies identify CXCR3-mediated trafficking at the tumour vascular interface as a critical checkpoint to effective T-cell-based cancer immunotherapy.

• 出版日期2015-6